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Comparison of postprandial (lunch tolerance) and postglucose (oral glucose tolerance) blood sugar values in pregnancy
Europ. J. Obstet, Gynec. reprod. Biol., 1980, 10/3, 163-171 0 Elsevier/North-Holland Biomedical Press
163
COMPARISON OF POSTPRANDIAL (LUNCH TOLERANCE) AND POSTGLUCOSE (ORAL GLUCOSE TOLERANCE) BLOOD SUGAR VALUES IN PREGNANCY
J.K. RADDER and J. TERPSTRA Diabetes Department,
University Hospital, Leiden, The Netherlands
Accepted for publication
12 September
1079
RADDER, J.K. and TERPSTRA, J. (1980): Comparison of postprandial (lunch tolerance) and postglucose (oral glucose tolerance) blood sugar values in pregnancy. Europ. J. Obstet. Gynec. reprod. Biol., 10/3, 163-171. The diagnosis of diabetes mellitus in pregnancy is generally made by means of an oral glucose tolerance test (oGTT). As this test can be unpleasant for pregnant women because of morning sickness, especially when frequent repetitions are necessary (in cases of suspected diabetes whereby a normal glucose tolerance can change into glucose intolerance as pregnancy progresses), we investigated whether the blood sugar values around lunch time, which we make use of in gestational diabetics to check the effect of treatment on the blood sugar level, could be used for diagnostic purposes. The normal upper limits of the capillary blood sugar values 30 min before and 60 and 90 min after a normal lunch (lunch tolerance test, L’IT) were determined. They were found to be 5.6, 7.6 and 7.2 mmol/l, respectively, for true blood sugar (Nelson Somogyi method) and 5.1, 6.6 and 6.4 mmol/l, respectively, for true blood glucose (glucose oxidase method). The normal upper limit of the sum of the component LTT values (ZL’M’) was 19.0 mmol/l for blood sugar and 17.1 mmol/l for blood glucose. It did not appear necessary to standardize the lunch, as the height of the blood sugar level after the lunch or ZL’M’ was not influenced by the size or composition of the lunch. The use of the L’IT for diagnostic purposes appeared to be warranted, since the reproducibility and the sensitivity of the LTI’ were at least as good as those of the oGTT. The diagnosis of diabetes mellitus in pregnancy is made when the normal upper limit of ZLTI’ or of one of the 3 LTT values is exceeded on two successive occasions within 3 wk, in order to avoid possible errors, lunch tolerance test; oral glucose tolerance test; pregnancy
INTRODUCTION
The diagnosis of diabetes mellitus in pregnancy is generally made by means of an oral glucose tolerance test (oGTT) (O’Sullivan and Mahan, 1964; Hadden, 1975; Heisig, 1975). As this test can be unpleasant for pregnant women because of morning sickness and duties at home, especially when frequent repetitions are necessary in cases of suspected diabetes, whereby a normal glucose tolerance can change into glucose intolerance as
164
pregnancy progresses, we investigated whether the blood sugar values around lunch time, which we make use of in gestational diabetics to check the effect of treatment on the blood sugar level, could be used for diagnostic purposes. Blood sugar values around lunch time have been found to be a reflection of the blood sugar level during the whole day (GBschke et al., 1974; Loreti et al., 1974; Molnar et al., 1974). The normal upper limit of the capillary blood sugar values 30 min before and 60 and 90 min after a normal lunch (lunch tolerance test, L’IT) were determined. The intervals of 60 and 90 min after the lunch were chosen because at those times maximum blood sugar values could be expected (Kopf et al., 1973). For the oGTT the maximum values have been reported to be influenced only slightly, if at all, by the size of the glucose load (Castro et al., 1970; Chandalia and Boshell, 1970; Sisk et al., 1970; Christensen et al., 1972; Fijrster et al., 1972; de Nobel and van’t Laar, 1978). For the LTT we also did not find a relationship between the blood sugar values after the lunch and the size or composition of the lunch. Consequently we did not standardize the lunch. The reproducibility and the sensitivity of the LTT were compared with those of the oGTT. MATERIALS
AND METHODS (Table I)
51 healthy women in the third trimester of pregnancy (group I) had a LTT and an oGTT with an interval of a week. Their mean age was 23 yr (range 17-31); the mean number of pregnancies was 1.3 (range l-3). They had a normal body weight in the non-pregnant state (i.e. less than 120% of ideal body weight, as calculated from the Metropolitan Life Insurance Company tables (Wissenschaftliche Tabellen, 1968b)), no diabetes in the family to the fourth degree, and normal pregnancies, including the present one, i.e. no abortions (more than two in succession), immature deliveries, stillbirths and/or heavy-for-date babies (weighing more than 4 kg at term). The oGTTs of these women (with one exception) were normal by wellestablished criteria (O’Sullivan and Mahan, 1964). Their LTT data were used for the calculation of the normal upper limits of the LIT.
TABLE I DATA OF THE GROUPS STUDIED Group
No. of females per group
Characteristic
of group
I II III IV
51 10 20 10
pregnant; normal non-pregnant; normal pregnant; suspected diabetes pregnant; suspected diabetes
Aim of study
LTT, L’IT, L’IT, LTT,
oGl”I’, normal upper limit reproducibility oGTI’, sensitivity significance of component values
165
The reproducibility of the LTI’ was tested in 10 healthy nulliparous female technicians, of the same age as group I, who were not pregnant and did not use oral contraceptive agents (group II). Each of them underwent the test 5 times within a fortnight. The sensitivity of the LTT in detecting glucose intolerance was tested in 20 women in the third trimester of pregnancy suspected of having diabetes because of glycosuria, a family history of diabetes and/or abnormal pregnancies (group III). For this purpose the LTT and oGTT of the women of group III were compared and related to the data for the normal women in group I. The mean age of the women in group III was 28 yr (range 20-40); the mean number of pregnancies was 2.4 (range l-4). Group III differed from group I with respect to age and parity (P < 0.01). We also investigated the significance of the component values of the LTT in a group of 10 pregnant women suspected of having diabetes because of glycosuria, a family history of diabetes and/or abnormal pregnancies (group IV). 87_ LTTs were performed (range per person 5-14). The mean age of these women was 29 yr (range 23-38) and the mean number of pregnancies 2.5 (range l-4). The LTT was carried out in our outpatient department, where the women arrived just before 11.30 a.m. A normal lunch was consumed between 12.00 noon and 12.15 p.m. At 11.30 a.m., 1.00 p.m. and 1.30 p.m. capillary blood samples were drawn from a fingertip. True blood sugar as well as true blood glucose was determined for group I in order to establish the normal values for each method (Seltzer, 1970). Both determinations were also made for group II. For groups III and IV only blood glucose was estimated, because the blood sugar determination was no longer available. The lunch supplied about 575 Cal (range 300~850), and contained 25 g (range 10-40) protein, 25 g (range 10-40) fat and 60 g (range 30-90) carbohydrates. The percentage of disaccharide (sucrose and lactose) in the carbohydrates varied from 0 to 40% (mean 20). The lunch contained approximately 50 g glucose equivalents from starch, sucrose and lactose (range 25-75). The women consumed at least 150 g of carbohydrates daily in the week prior to the test. Excessive physical activity during the test was avoided. The oGTT was performed in the morning after an overnight fast under the conditions recommended by the World Health Organization (WHO techn. Rep. Ser., 1965a). Capillary blood samples were drawn from a fingertip in the fasting state and every half-hour for 2.5 h after a 100 g glucose load. For group I true blood sugar was determined, for group III true blood glucose. In order to be able to compare the oGTT values of both groups, these were corrected for the difference between blood sugar and blood glucose. True blood sugar was determined according to the method of Nelson and Somogyi (Nelson, 1944; Somogyi, 1945a, b) and true blood glucose with the glucose oxidase method (van der Slik et al., 1970) in whole blood. The classification of diabetes mellitus is in accordance with that of the World Health Organization (WHO techn. Rep. Ser., 1965b) and the British Diabetic Association (FitzGerald and Keen, 1964).
4.7 4.1-5.7 0.4 0.2-1.0
4.8 4.74.9 0.6 0.4-0.9
6.3 5.7-6.7 1.2 0.8-1.4
means and standard
6.2 5.3-8-O 1.0 0.2-1.3
1.00 p.m.
5.5 5.2-5.9 1.1 0.8-1.2
deviations
5.4 4.2-7.0 0.6 0.1-1.1
1.30 p.m.
** 3.9 -+ 0.6 5.1
11.30 a.m.
4.2 3.7-5.2 0.4 0.3-0.8
11.30 a.m.
16.5 15.7-17.6 1.8 1.42.5
*
5.5 5.1-5.8 1.0 0.7-l .2
*
5.4 4.8-6.4 0.7 0.3-1.3
1.00 p.m.
LlTs
LTT values.
4.3 4.2-4.6 0.6 0.5-0.8
(SD) for group ZZ in 5 successive
16.5 14.8-19.4 1.6 0.62.3
ZLTT **
Glucose oxidase
LTTs
5.3 -+ 0.7 6.6
1.00 p.m.
(SD) for group ZZ in 5 successive
16.0 -+ 1.5 19.0
ZLTr
Glucose oxidase
* Values are expressed in mmol/l in capillary blood. ** ZLTT = sum of component
Median of mean Range of mean Median of SD Range of SD
B: Median and range of group
Median of mean Range of mean Median of SD Range of SD
11.30 a.m.
deviations
LTI’ values.
5.7 _+0.8 7.2
1.30 p.m.
means and standard
Nelson Somogyi
A: Median and range of individual
TABLE III
6.0 _+0.8 7.6
1.00 p.m.
= sum of component
4.3 _+0.7 5.6
11.30 a.m.
Nelson Somogyi
FOR GROUP I *
* Capillary blood. ** ELTl
Mean -+ SD Normal upper limit
LTT VALUES (mmol/l)
TABLE II
4.8 4.64.9 0.8 0.44.9
4.8 3.8-5.6 0.4 O-2-0.7
1.30 p.m.
5.0 -+ 0.7 6.4
1.30 p.m.
1.5
14.6 14.1-15.3 1.8 l.O1.9
14.7 12.8-16.2 1.2 o-4- 2.2
XLTT **
14.1+ 17.1
XLTT **
z Q)
167
The upper limit was defined as the upper 95% tolerance limit with a confidence coefficient of 95% (Wissenschaftliche Tabellen, 1968a). Statistical analysis of the data was performed according to the sign test, regression analysis and analysis of covariance. RESULTS
Normal upper limits of the LTT The upper limits of the LTT values for the normal pregnant women of group I were 5.6, 7.6 and 7.2 mmol/l for blood sugar and 5.1, 6.6 and 6.4 for blood glucose, respectively. The normal upper limit of the sum of the component LTT values (EL’I’T) was 19.0 mmol/l for blood sugar and 17.1 mmol/l for blood glucose (Table II). We did not find a relationship between the blood sugar or glucose values after the lunch or ZLTT and the size or composition of the lunch. Reproducibility of the LTT The reproducibility of the LTT per individual was indicated by the individual standard deviations for the 10 non-pregnant females of group II (Table IIIA). Because the investigated group II was small, the reproducibility for the group as a whole (Table IIIB) could not be expected to be better than that per individual. Sensitivity of the LTT In order to be able to compare the LTT and the oGTT of group III with respect to sensitivity, the tests were characterized by one symbol: the sum of the component blood glucose values (ZLTT and EoGTT, respectively). XL.T.1.
I
mm&/l
L
upprr
nonnol
l
limit
IS
.
: .
l
. .
l
. I .
.
.
. I norm*l limit
upper
.
25
30
35
I -T--v-10
l -T-T-.
&5
f o. G.T.T. mmol/I
Fig. 1. Sum of the LTT and sum of the oGTT blood glucose values for the pregnant females with suspected diabetes (group III) and their relation to the normal upper limit of these values.
168
The upper limits for ZLTT and EoGTT of group I were used as normal values. The sensitivity of one test with respect to the other in detecting glucose intolerance was assumed to be greater if the normal upper limit for one test was exceeded more often than that of the other. In group III the sensitivity of the LTT was found to be greater than that of the oGTT (P < 0.05) (Fig. 1). Moreover, the ZLTTs of group III were higher than those of group I after correction for the difference between the CoGTTs of the two groups (P < 0.01 by analysis of covariance). From these data it can be concluded that the sensitivity of the LTT in detecting glucose intolerance in pregnant women suspected of having diabetes is greater than that of the oGTT. Significance of the component values of the LTT The normal upper limit of one or more of the LTT values and/or the CLTT was exceeded in 41 of the 87 LTTs of group IV (range of abnormal LTTs per person, O-11). If one of the LTT values was abnormal, the ZLTT was in most cases also abnormal (Table 4a and b), whereas abnormalities of more than one LTT value and of the ZLTT were always related (Table 4~). The normal upper limit for the ZLTT was exceeded 33 times. This was about as frequent as the occurrence of abnormalities in one of the 3 LTT values (Table 4b). Thus it seems that the best way to use the LTT as a diagnostic tool is to calculate XLTT. An abnormality in one of the 3 LTT values, however, appears to be as indicative.
TABLE IV NUMBER LIMIT
OF LTT VALUES
OF GROUP
IV EXCEEDING
THE NORMAL
LTT values *
n
LTT values *
n
Ul
22 19 21 33
1+x 2+x 3+x
17 19 19
34 38 26 39 41
lor2+Z lor3+Z 2or3+;I: lor2or3+Z
29 31 24 32
I 5 14 3
1+2+x 1+3+x 2+3+z 1 +2 + 3 +%
7 5 14 3
2 i blor2 1 or 2 or 1 or 1 or
3 3 2 or 3 2 or 3 or Z
cl+2 1+3 2+3 1+2+3
UPPER
* LTT value 1 = LTT value at 11.30 a.m.; LTT value 2 = LTT value at 1.00 p.m.; LTT value 3 = LTT value at 1.30 p.m.; L’lT value x = sum of LTI’ values 1,2 and 3.
169 DISCUSSION
We have developed a simple test (the lunch tolerance test, LTT) in order to detect and manage glucose intolerance in pregnancy. For that purpose the normal upper limit of ZLTT or of one of the 3 LTT values can be used. For the oGTT the sum and the component values have also been reported to have similar significance (Danowski et al., 1970; Kijbberling and Creutzfeldt, 1970). We generally use the postprandial values of the LTT. In order to avoid possible errors, the diagnosis of diabetes mellitus in pregnancy is only established whenever these values are increased on two successive occasions within 3 wk. A practical advantage of the LTT is that it does not appear necessary to standardize the lunch, probably because we made use of the maximum blood sugar or glucose values after the lunch. The use of the LTT instead of the oGTT for the detection of glucose intolerance in pregnancy is warranted, since we have shown that the reproducibility of the LTT is in the same order of magnitude as the reproducibility of the oGTT, as reported in the literature (McDonald et al., 1965, 1969; O’Sullivan and Mahan, 1966; Lind et al., 1968; Toeller and Knussman, 1973). We felt that we were justified in involving non-pregnant women for the study of the reproducibility of the LTT, because we are not aware of differences in reproducibility of laboratory tests between pregnant and non-pregnant women. For glucose tolerance tests, at any rate, the reproducibility has been reported to be in the same order of magnitude in both states (O’Sullivan and Mahan, 1966); furthermore, differences in sex, age, weight and parity did not seem to be influential (McDonald et al., 1965, 1969; Lind et al., 1968; Toeller and Knussman, 1973). The sensitivity of the LTT appears to be even greater than that of the oGTT. This finding proved to be real, since, in women with abnormal LTTs in pregnancy but with a normal glucose tolerance test after delivery, i.e. in latent diabetics, we were able to demonstrate a diminished insulin secretion during the i.v. glucose tolerance test in the non-pregnant state (Radder, 1977). Although group III differs from group I with respect to age and parity, it seems unlikely that these differences interfere with the results of the study of the sensitivity of the LTT. As far as age is concerned, it has been argued that the criteria for normal postprandial blood sugar values need not be adapted (O’Sullivan and Mahan, 1971). So it can be assumed that the normal blood sugar values of group I are also valid for women of the age of group III. Whether a difference in parity affects blood sugar values is not known. The normal upper limits of the LTT, as calculated for the third trimester, are used during the whole course of pregnancy, as there is no agreement as yet about whether postprandial blood sugar values decrease or increase as pregnancy progresses. In one report it was stated that not only the fasting but also the non-fasting blood glucose levels decrease throughout the course of pregnancy (Victor, 1974). On the other hand, others have found lower preprandial but higher postprandial blood glucose values as pregnancy progressed (Gillmer et al., 1975).
170
In conclusion, the lunch tolerance test appears to be a simple and reliable test for diagnostic as well as therapeutic purposes in pregnancy. This test seems to be an improvement on the oral glucose tolerance test. ACKNOWLEDGEMENTS
We owe thanks to the Department of Obstetrics and Gynecology of the University Hospital at Leiden (heads: Prof. Dr. J. Bennebroek Gravenhorst and Prof. Dr. E.V. van Hall; former head: Prof. Dr. A. Sikkel) and especially the midwives (head: Mrs. A.C. Jens) for helping us select the pregnant women, Prof. Dr. D. Smeenk for his valuable remarks, Drs. E.A. van de Velde for statistical analysis, Mrs. A. Cornelius-von Franquemont for technical assistance, Miss B. Versteeg for secretarial help and Mrs. G.P. BiegerSmith for correcting the English text. The Organization for Health Research T.N.O. lent financial support. REFERENCES Castro, A., Scott, J.P., Grettie, D.P., Macfarlane, D. and Bailey, R.E. (1970): Plasma insulin and glucose responses of healthy subjects to varying glucose loads during three-hour oral glucose tolerance tests. Diabetes, 19, 842. Chandalia, H.B. and Boshell, B.R. (1970): Diagnosis of diabetes. The size and nature of carbohydrate load. Diabetes, 19, 863. Christensen, N.J., Brskov, H. and Hansen, A.P. (1972): Significance of glucose load in oral glucose tolerance tests. Acta med. stand.. 192, 337. Danowski, T.S., Aarons, J.H., Hydovitz, J.D. and Wingert, J.P. (1970): Utility of equivocal glucose tolerances. Diabetes, 19, 524. FitzGerald, M.G. and Keen, H. (1964): Diagnostic classification of diabetes. Lance& 1, 1325. FSrster, H., Haslbeck, M. and Mehnert, H. (1972): Metabolic studies following the oral ingestion of different doses of glucose. Diabetes, 21, 1102. Gillmer, M.D.G., Beard, R.W., Brooke, F.M. and Oakley, N.W. (1975): Carbohydrate metabolism in pregnancy. Part I - Diurnal plasma glucose profile in normal and diabetic women. Brit. med. J., 3, 399. Giischke, H., Denes, A., Girard, J., Collard, F. and Berger, W. (1974): Circadian variations of carbohydrate tolerance in maturity-onset diabetics treated with sulfonylureas.
Horm. metab. Res., 6, 386. Hadden, D.R. (1975):
Glucose tolerance tests in pregnancy. In: Carbohydrate MetaboZism p. 19. Editors: H.W. Sutherland and J.M. Stowers. Churchill-Living&one, Edinburgh, London, New York. Heisig, N. (1975): Glukosetoleranztests und andere Belastungsverfahren. Oraler Glukosetoleranztest. In: Diabetes und Schwangerschnft, p. 11. Georg Thieme Verlag, Stuttgart. KSbberling, J. and Creutzfeldt, W. (1970): Comparison of different methods for the evaluation of the oral glucose tolerance test. Diabetes, 19, 870. Kopf, A., Tchobroutsky, G. and Eschwege, E. (1973): Serial postprandial blood glucose levels in 309 subjects with and without diabetes. Diabetes, 22, 834. Lind, T., Cheyne, G.A., Billewics, W.Z. and Fairweather, D.V.I. (1968): Observations on the oral glucose tolerance test in pregnancy. J. Obstet. Gynaec. Brit. Cwlth, 75, 540. Loreti, L., Sugase, T. and FOB, P.P. (1974): Diurnal variations of serum insulin, total glucagon, cortisol, glucose and free fatty acids in normal and diabetic subjects before and after treatment with chlorpropamide. Horm. Res., 5, 278.
in Pregnancy and the Newborn,
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McDonald, G.W., Fisher, G.F. and Burnham, C.E. (1965): Reproducibility of the oral glucose tolerance test. Diabetes, 14, 473. McDonald, G.W., Burham, C.E. and Lewis, W.F. (1969): Reproducibility of glucose tolerance in 101 nondiabetic women. Publ. Hlth Rep., 84, 353. Molnar, G.D., Taylor, W.F. and Langworthy, A. (1974): On measuring the adequacy of diabetes regulation: comparison of continuously monitored blood glucose patterns with values at selected time points. Diabetologia, 10, 139. Nelson, N. (1944): A photometric adaption of the Somogyi method for the determination of glucose. J. biol. Chem., 153, 375. de Nobel, E. and van’t Laar, A. (1978): The size of the loading dose as an important determinant of the results of the oral glucose tolerance test. A study in subjects with slightly impaired glucose tolerance. Diabetes, 27, 42. O’Sullivan, J.B. and Mahan, C.M. (1964): Criteria for the oral glucose tolerance test in pregnancy. Diabetes, 13, 278. O’Sullivan, J.B. and Mahan, CM. (1966): Glucose tolerance test. Variability in pregnant and non-pregnant women. Amer. J. clin. Nutr., 19, 345. O’Sullivan, J.B. and Mahan, C.M. (1971): Evaluation of age-adjusted criteria for potential diabetes. Diabetes, 20, 811. Radder, J.K. (1977): The intravenous glucose tolerance test as a tool to distinguish latent diabetics from non-diabetics. The reflection of slightly impaired insulin secretion on the blood sugar level. In: Early Stages of Diabetes Mellitus, p. 57. Thesis, Leiden. Seltzer, H.S. (1970): Diagnosis of diabetes. Methods for determining blood glucose. In: Diabetes Mellitus: Theory and Practice, p. 442. Editors: M. Ellenberg and H. Rifkin. McGraw-Hill, New York, Sisk, C.W., Burnham, C.E., Stewart, J. and McDonald, G.W. (1970): Comparison of the 50 and 100 gram oral glucose tolerance test. Diabetes, 19, 852. van der Slik, W., Koevoet, A.L., van Neerbos, B.R., Alkemade, G.M. and van der Harst, P. (1970): A modified automated enzymatic glucose determination. Clin. chim. Acta,
27, 325. Somogyi,
M. (1945a):
A new reagent
for the determination
of sugars. J. biol Chem., 160,
61. Somogyi, M. (1954b):
Determination of blood sugar. J. biol. Chem., 160, 69. Toeller, M. and Knussmann, R. (1973): Reproducibility of oral glucose tolerance tests with three different loads. Diabetologia, 9, 102. Victor, A. (1974): Normal blood sugar variation during pregnancy. Acta obstet. gynec.
stand., 53, 37. Wissenschaftliche Tabellen, 7th edn, Base1 (1968a): J.R. Geigy, A.G., Pharma, p. 45. Wissenschaftliche Tabellen, 7th edn, Base1 (1968b): J.R. Geigy, A.G., Pharma, p. 701. Wld Hlth Org. techn. Rep. Ser. (1965a): Diabetes mellitus. Report of a WHO Expert Committee. Definition of laboratory criteria in the diagnosis of diabetes mellitus.
WHO, 310, 9. Wld Hlth Org. techn. Rep. Ser. (1965b): Committee. Classes of diabetes mellitus.
Diabetes
mellitus.
WHO, 310, 13.
Report
of a WHO Expert
163
COMPARISON OF POSTPRANDIAL (LUNCH TOLERANCE) AND POSTGLUCOSE (ORAL GLUCOSE TOLERANCE) BLOOD SUGAR VALUES IN PREGNANCY
J.K. RADDER and J. TERPSTRA Diabetes Department,
University Hospital, Leiden, The Netherlands
Accepted for publication
12 September
1079
RADDER, J.K. and TERPSTRA, J. (1980): Comparison of postprandial (lunch tolerance) and postglucose (oral glucose tolerance) blood sugar values in pregnancy. Europ. J. Obstet. Gynec. reprod. Biol., 10/3, 163-171. The diagnosis of diabetes mellitus in pregnancy is generally made by means of an oral glucose tolerance test (oGTT). As this test can be unpleasant for pregnant women because of morning sickness, especially when frequent repetitions are necessary (in cases of suspected diabetes whereby a normal glucose tolerance can change into glucose intolerance as pregnancy progresses), we investigated whether the blood sugar values around lunch time, which we make use of in gestational diabetics to check the effect of treatment on the blood sugar level, could be used for diagnostic purposes. The normal upper limits of the capillary blood sugar values 30 min before and 60 and 90 min after a normal lunch (lunch tolerance test, L’IT) were determined. They were found to be 5.6, 7.6 and 7.2 mmol/l, respectively, for true blood sugar (Nelson Somogyi method) and 5.1, 6.6 and 6.4 mmol/l, respectively, for true blood glucose (glucose oxidase method). The normal upper limit of the sum of the component LTT values (ZL’M’) was 19.0 mmol/l for blood sugar and 17.1 mmol/l for blood glucose. It did not appear necessary to standardize the lunch, as the height of the blood sugar level after the lunch or ZL’M’ was not influenced by the size or composition of the lunch. The use of the L’IT for diagnostic purposes appeared to be warranted, since the reproducibility and the sensitivity of the LTI’ were at least as good as those of the oGTT. The diagnosis of diabetes mellitus in pregnancy is made when the normal upper limit of ZLTI’ or of one of the 3 LTT values is exceeded on two successive occasions within 3 wk, in order to avoid possible errors, lunch tolerance test; oral glucose tolerance test; pregnancy
INTRODUCTION
The diagnosis of diabetes mellitus in pregnancy is generally made by means of an oral glucose tolerance test (oGTT) (O’Sullivan and Mahan, 1964; Hadden, 1975; Heisig, 1975). As this test can be unpleasant for pregnant women because of morning sickness and duties at home, especially when frequent repetitions are necessary in cases of suspected diabetes, whereby a normal glucose tolerance can change into glucose intolerance as
164
pregnancy progresses, we investigated whether the blood sugar values around lunch time, which we make use of in gestational diabetics to check the effect of treatment on the blood sugar level, could be used for diagnostic purposes. Blood sugar values around lunch time have been found to be a reflection of the blood sugar level during the whole day (GBschke et al., 1974; Loreti et al., 1974; Molnar et al., 1974). The normal upper limit of the capillary blood sugar values 30 min before and 60 and 90 min after a normal lunch (lunch tolerance test, L’IT) were determined. The intervals of 60 and 90 min after the lunch were chosen because at those times maximum blood sugar values could be expected (Kopf et al., 1973). For the oGTT the maximum values have been reported to be influenced only slightly, if at all, by the size of the glucose load (Castro et al., 1970; Chandalia and Boshell, 1970; Sisk et al., 1970; Christensen et al., 1972; Fijrster et al., 1972; de Nobel and van’t Laar, 1978). For the LTT we also did not find a relationship between the blood sugar values after the lunch and the size or composition of the lunch. Consequently we did not standardize the lunch. The reproducibility and the sensitivity of the LTT were compared with those of the oGTT. MATERIALS
AND METHODS (Table I)
51 healthy women in the third trimester of pregnancy (group I) had a LTT and an oGTT with an interval of a week. Their mean age was 23 yr (range 17-31); the mean number of pregnancies was 1.3 (range l-3). They had a normal body weight in the non-pregnant state (i.e. less than 120% of ideal body weight, as calculated from the Metropolitan Life Insurance Company tables (Wissenschaftliche Tabellen, 1968b)), no diabetes in the family to the fourth degree, and normal pregnancies, including the present one, i.e. no abortions (more than two in succession), immature deliveries, stillbirths and/or heavy-for-date babies (weighing more than 4 kg at term). The oGTTs of these women (with one exception) were normal by wellestablished criteria (O’Sullivan and Mahan, 1964). Their LTT data were used for the calculation of the normal upper limits of the LIT.
TABLE I DATA OF THE GROUPS STUDIED Group
No. of females per group
Characteristic
of group
I II III IV
51 10 20 10
pregnant; normal non-pregnant; normal pregnant; suspected diabetes pregnant; suspected diabetes
Aim of study
LTT, L’IT, L’IT, LTT,
oGl”I’, normal upper limit reproducibility oGTI’, sensitivity significance of component values
165
The reproducibility of the LTI’ was tested in 10 healthy nulliparous female technicians, of the same age as group I, who were not pregnant and did not use oral contraceptive agents (group II). Each of them underwent the test 5 times within a fortnight. The sensitivity of the LTT in detecting glucose intolerance was tested in 20 women in the third trimester of pregnancy suspected of having diabetes because of glycosuria, a family history of diabetes and/or abnormal pregnancies (group III). For this purpose the LTT and oGTT of the women of group III were compared and related to the data for the normal women in group I. The mean age of the women in group III was 28 yr (range 20-40); the mean number of pregnancies was 2.4 (range l-4). Group III differed from group I with respect to age and parity (P < 0.01). We also investigated the significance of the component values of the LTT in a group of 10 pregnant women suspected of having diabetes because of glycosuria, a family history of diabetes and/or abnormal pregnancies (group IV). 87_ LTTs were performed (range per person 5-14). The mean age of these women was 29 yr (range 23-38) and the mean number of pregnancies 2.5 (range l-4). The LTT was carried out in our outpatient department, where the women arrived just before 11.30 a.m. A normal lunch was consumed between 12.00 noon and 12.15 p.m. At 11.30 a.m., 1.00 p.m. and 1.30 p.m. capillary blood samples were drawn from a fingertip. True blood sugar as well as true blood glucose was determined for group I in order to establish the normal values for each method (Seltzer, 1970). Both determinations were also made for group II. For groups III and IV only blood glucose was estimated, because the blood sugar determination was no longer available. The lunch supplied about 575 Cal (range 300~850), and contained 25 g (range 10-40) protein, 25 g (range 10-40) fat and 60 g (range 30-90) carbohydrates. The percentage of disaccharide (sucrose and lactose) in the carbohydrates varied from 0 to 40% (mean 20). The lunch contained approximately 50 g glucose equivalents from starch, sucrose and lactose (range 25-75). The women consumed at least 150 g of carbohydrates daily in the week prior to the test. Excessive physical activity during the test was avoided. The oGTT was performed in the morning after an overnight fast under the conditions recommended by the World Health Organization (WHO techn. Rep. Ser., 1965a). Capillary blood samples were drawn from a fingertip in the fasting state and every half-hour for 2.5 h after a 100 g glucose load. For group I true blood sugar was determined, for group III true blood glucose. In order to be able to compare the oGTT values of both groups, these were corrected for the difference between blood sugar and blood glucose. True blood sugar was determined according to the method of Nelson and Somogyi (Nelson, 1944; Somogyi, 1945a, b) and true blood glucose with the glucose oxidase method (van der Slik et al., 1970) in whole blood. The classification of diabetes mellitus is in accordance with that of the World Health Organization (WHO techn. Rep. Ser., 1965b) and the British Diabetic Association (FitzGerald and Keen, 1964).
4.7 4.1-5.7 0.4 0.2-1.0
4.8 4.74.9 0.6 0.4-0.9
6.3 5.7-6.7 1.2 0.8-1.4
means and standard
6.2 5.3-8-O 1.0 0.2-1.3
1.00 p.m.
5.5 5.2-5.9 1.1 0.8-1.2
deviations
5.4 4.2-7.0 0.6 0.1-1.1
1.30 p.m.
** 3.9 -+ 0.6 5.1
11.30 a.m.
4.2 3.7-5.2 0.4 0.3-0.8
11.30 a.m.
16.5 15.7-17.6 1.8 1.42.5
*
5.5 5.1-5.8 1.0 0.7-l .2
*
5.4 4.8-6.4 0.7 0.3-1.3
1.00 p.m.
LlTs
LTT values.
4.3 4.2-4.6 0.6 0.5-0.8
(SD) for group ZZ in 5 successive
16.5 14.8-19.4 1.6 0.62.3
ZLTT **
Glucose oxidase
LTTs
5.3 -+ 0.7 6.6
1.00 p.m.
(SD) for group ZZ in 5 successive
16.0 -+ 1.5 19.0
ZLTr
Glucose oxidase
* Values are expressed in mmol/l in capillary blood. ** ZLTT = sum of component
Median of mean Range of mean Median of SD Range of SD
B: Median and range of group
Median of mean Range of mean Median of SD Range of SD
11.30 a.m.
deviations
LTI’ values.
5.7 _+0.8 7.2
1.30 p.m.
means and standard
Nelson Somogyi
A: Median and range of individual
TABLE III
6.0 _+0.8 7.6
1.00 p.m.
= sum of component
4.3 _+0.7 5.6
11.30 a.m.
Nelson Somogyi
FOR GROUP I *
* Capillary blood. ** ELTl
Mean -+ SD Normal upper limit
LTT VALUES (mmol/l)
TABLE II
4.8 4.64.9 0.8 0.44.9
4.8 3.8-5.6 0.4 O-2-0.7
1.30 p.m.
5.0 -+ 0.7 6.4
1.30 p.m.
1.5
14.6 14.1-15.3 1.8 l.O1.9
14.7 12.8-16.2 1.2 o-4- 2.2
XLTT **
14.1+ 17.1
XLTT **
z Q)
167
The upper limit was defined as the upper 95% tolerance limit with a confidence coefficient of 95% (Wissenschaftliche Tabellen, 1968a). Statistical analysis of the data was performed according to the sign test, regression analysis and analysis of covariance. RESULTS
Normal upper limits of the LTT The upper limits of the LTT values for the normal pregnant women of group I were 5.6, 7.6 and 7.2 mmol/l for blood sugar and 5.1, 6.6 and 6.4 for blood glucose, respectively. The normal upper limit of the sum of the component LTT values (EL’I’T) was 19.0 mmol/l for blood sugar and 17.1 mmol/l for blood glucose (Table II). We did not find a relationship between the blood sugar or glucose values after the lunch or ZLTT and the size or composition of the lunch. Reproducibility of the LTT The reproducibility of the LTT per individual was indicated by the individual standard deviations for the 10 non-pregnant females of group II (Table IIIA). Because the investigated group II was small, the reproducibility for the group as a whole (Table IIIB) could not be expected to be better than that per individual. Sensitivity of the LTT In order to be able to compare the LTT and the oGTT of group III with respect to sensitivity, the tests were characterized by one symbol: the sum of the component blood glucose values (ZLTT and EoGTT, respectively). XL.T.1.
I
mm&/l
L
upprr
nonnol
l
limit
IS
.
: .
l
. .
l
. I .
.
.
. I norm*l limit
upper
.
25
30
35
I -T--v-10
l -T-T-.
&5
f o. G.T.T. mmol/I
Fig. 1. Sum of the LTT and sum of the oGTT blood glucose values for the pregnant females with suspected diabetes (group III) and their relation to the normal upper limit of these values.
168
The upper limits for ZLTT and EoGTT of group I were used as normal values. The sensitivity of one test with respect to the other in detecting glucose intolerance was assumed to be greater if the normal upper limit for one test was exceeded more often than that of the other. In group III the sensitivity of the LTT was found to be greater than that of the oGTT (P < 0.05) (Fig. 1). Moreover, the ZLTTs of group III were higher than those of group I after correction for the difference between the CoGTTs of the two groups (P < 0.01 by analysis of covariance). From these data it can be concluded that the sensitivity of the LTT in detecting glucose intolerance in pregnant women suspected of having diabetes is greater than that of the oGTT. Significance of the component values of the LTT The normal upper limit of one or more of the LTT values and/or the CLTT was exceeded in 41 of the 87 LTTs of group IV (range of abnormal LTTs per person, O-11). If one of the LTT values was abnormal, the ZLTT was in most cases also abnormal (Table 4a and b), whereas abnormalities of more than one LTT value and of the ZLTT were always related (Table 4~). The normal upper limit for the ZLTT was exceeded 33 times. This was about as frequent as the occurrence of abnormalities in one of the 3 LTT values (Table 4b). Thus it seems that the best way to use the LTT as a diagnostic tool is to calculate XLTT. An abnormality in one of the 3 LTT values, however, appears to be as indicative.
TABLE IV NUMBER LIMIT
OF LTT VALUES
OF GROUP
IV EXCEEDING
THE NORMAL
LTT values *
n
LTT values *
n
Ul
22 19 21 33
1+x 2+x 3+x
17 19 19
34 38 26 39 41
lor2+Z lor3+Z 2or3+;I: lor2or3+Z
29 31 24 32
I 5 14 3
1+2+x 1+3+x 2+3+z 1 +2 + 3 +%
7 5 14 3
2 i blor2 1 or 2 or 1 or 1 or
3 3 2 or 3 2 or 3 or Z
cl+2 1+3 2+3 1+2+3
UPPER
* LTT value 1 = LTT value at 11.30 a.m.; LTT value 2 = LTT value at 1.00 p.m.; LTT value 3 = LTT value at 1.30 p.m.; L’lT value x = sum of LTI’ values 1,2 and 3.
169 DISCUSSION
We have developed a simple test (the lunch tolerance test, LTT) in order to detect and manage glucose intolerance in pregnancy. For that purpose the normal upper limit of ZLTT or of one of the 3 LTT values can be used. For the oGTT the sum and the component values have also been reported to have similar significance (Danowski et al., 1970; Kijbberling and Creutzfeldt, 1970). We generally use the postprandial values of the LTT. In order to avoid possible errors, the diagnosis of diabetes mellitus in pregnancy is only established whenever these values are increased on two successive occasions within 3 wk. A practical advantage of the LTT is that it does not appear necessary to standardize the lunch, probably because we made use of the maximum blood sugar or glucose values after the lunch. The use of the LTT instead of the oGTT for the detection of glucose intolerance in pregnancy is warranted, since we have shown that the reproducibility of the LTT is in the same order of magnitude as the reproducibility of the oGTT, as reported in the literature (McDonald et al., 1965, 1969; O’Sullivan and Mahan, 1966; Lind et al., 1968; Toeller and Knussman, 1973). We felt that we were justified in involving non-pregnant women for the study of the reproducibility of the LTT, because we are not aware of differences in reproducibility of laboratory tests between pregnant and non-pregnant women. For glucose tolerance tests, at any rate, the reproducibility has been reported to be in the same order of magnitude in both states (O’Sullivan and Mahan, 1966); furthermore, differences in sex, age, weight and parity did not seem to be influential (McDonald et al., 1965, 1969; Lind et al., 1968; Toeller and Knussman, 1973). The sensitivity of the LTT appears to be even greater than that of the oGTT. This finding proved to be real, since, in women with abnormal LTTs in pregnancy but with a normal glucose tolerance test after delivery, i.e. in latent diabetics, we were able to demonstrate a diminished insulin secretion during the i.v. glucose tolerance test in the non-pregnant state (Radder, 1977). Although group III differs from group I with respect to age and parity, it seems unlikely that these differences interfere with the results of the study of the sensitivity of the LTT. As far as age is concerned, it has been argued that the criteria for normal postprandial blood sugar values need not be adapted (O’Sullivan and Mahan, 1971). So it can be assumed that the normal blood sugar values of group I are also valid for women of the age of group III. Whether a difference in parity affects blood sugar values is not known. The normal upper limits of the LTT, as calculated for the third trimester, are used during the whole course of pregnancy, as there is no agreement as yet about whether postprandial blood sugar values decrease or increase as pregnancy progresses. In one report it was stated that not only the fasting but also the non-fasting blood glucose levels decrease throughout the course of pregnancy (Victor, 1974). On the other hand, others have found lower preprandial but higher postprandial blood glucose values as pregnancy progressed (Gillmer et al., 1975).
170
In conclusion, the lunch tolerance test appears to be a simple and reliable test for diagnostic as well as therapeutic purposes in pregnancy. This test seems to be an improvement on the oral glucose tolerance test. ACKNOWLEDGEMENTS
We owe thanks to the Department of Obstetrics and Gynecology of the University Hospital at Leiden (heads: Prof. Dr. J. Bennebroek Gravenhorst and Prof. Dr. E.V. van Hall; former head: Prof. Dr. A. Sikkel) and especially the midwives (head: Mrs. A.C. Jens) for helping us select the pregnant women, Prof. Dr. D. Smeenk for his valuable remarks, Drs. E.A. van de Velde for statistical analysis, Mrs. A. Cornelius-von Franquemont for technical assistance, Miss B. Versteeg for secretarial help and Mrs. G.P. BiegerSmith for correcting the English text. The Organization for Health Research T.N.O. lent financial support. REFERENCES Castro, A., Scott, J.P., Grettie, D.P., Macfarlane, D. and Bailey, R.E. (1970): Plasma insulin and glucose responses of healthy subjects to varying glucose loads during three-hour oral glucose tolerance tests. Diabetes, 19, 842. Chandalia, H.B. and Boshell, B.R. (1970): Diagnosis of diabetes. The size and nature of carbohydrate load. Diabetes, 19, 863. Christensen, N.J., Brskov, H. and Hansen, A.P. (1972): Significance of glucose load in oral glucose tolerance tests. Acta med. stand.. 192, 337. Danowski, T.S., Aarons, J.H., Hydovitz, J.D. and Wingert, J.P. (1970): Utility of equivocal glucose tolerances. Diabetes, 19, 524. FitzGerald, M.G. and Keen, H. (1964): Diagnostic classification of diabetes. Lance& 1, 1325. FSrster, H., Haslbeck, M. and Mehnert, H. (1972): Metabolic studies following the oral ingestion of different doses of glucose. Diabetes, 21, 1102. Gillmer, M.D.G., Beard, R.W., Brooke, F.M. and Oakley, N.W. (1975): Carbohydrate metabolism in pregnancy. Part I - Diurnal plasma glucose profile in normal and diabetic women. Brit. med. J., 3, 399. Giischke, H., Denes, A., Girard, J., Collard, F. and Berger, W. (1974): Circadian variations of carbohydrate tolerance in maturity-onset diabetics treated with sulfonylureas.
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